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Review Topical Sections

Nanoparticles for the treatment of osteoporosis

  • Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical therapeutic treatments are not able to offer long-term solutions. Most of the clinically used anti-osteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and nanomaterials to create innovative and alternative treatments. One of the innovative approaches to enhance osteoporosis therapy and prevent potential adverse effects is the development of bone-targeting drug delivery technologies. It minimizes the systemic toxicity and also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us, including the stability and the toxicity issues. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery, require multidisciplinary collaboration between scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order to facilitate their clinical applications.

    Citation: P. Mora-Raimundo, M. Manzano, M. Vallet-Regí. Nanoparticles for the treatment of osteoporosis[J]. AIMS Bioengineering, 2017, 4(2): 259-274. doi: 10.3934/bioeng.2017.2.259

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  • Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical therapeutic treatments are not able to offer long-term solutions. Most of the clinically used anti-osteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and nanomaterials to create innovative and alternative treatments. One of the innovative approaches to enhance osteoporosis therapy and prevent potential adverse effects is the development of bone-targeting drug delivery technologies. It minimizes the systemic toxicity and also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us, including the stability and the toxicity issues. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery, require multidisciplinary collaboration between scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order to facilitate their clinical applications.


    Differential equations, especially those possessing non-negative solutions, play an important role in many areas of sciences such as biology [1,2,3,4,5], chemistry [6,7,8], epidemiology [9,10,11] or population dynamics [12,13,14] to name a few of these fields. Since we focus on examining a time-discrete, mathematical model of epidemiology in our work, we limit ourselves to a concise review of literature in this area.

    In this article, we want to consider the time-continuous non-autonomous susceptible-infected-recovered (SIR) model

    {S(t)=α(t)S(t)I(t)N,I(t)=α(t)S(t)I(t)Nβ(t)I(t),R(t)=β(t)I(t),S(0)=S0,I(0)=I0,R(0)=R0 (1.1)

    in epidemiology thoroughly investigated by Wacker and Schlüter in 2020 [15]. We provide further assumptions regarding this time-continuous model in Section 2. In 1927, one of the most famous papers in mathematical epidemiology, written by Kermack and McKendrick, was published [16]. Previously, Ross and Hudson proposed important foundations for epidemiological models [17,18]. Additional well-written books and review articles on mathematical epidemiology are authored by Hethcote [19] and Brauer and Castillo-Chávez [20]. Since the establishment of the classical SIR model, many modifications have been suggested and, due to the on-going COVID-19 pandemic, many articles have been published with respect to this topic and we can only summarize a brief selection of these works.

    To this day, there are works which provide closed solution formulas for simple models in epidemiology [21,22,23]. However, more articles consider numerical approximations due to appearing nonlinearities. Especially during the COVID-19 pandemic, different approaches have been published [15,24]. In 2022, Chen and co-authors suggested a susceptible-exposed-infected-unreported-recovered (SEIUR) model for the spread of COVID-19 with piecewise constant dynamical parameters [25] as one possible extension of classical SIR models. Taking age- and sex-structure of a population into account, Wacker and Schlüter proposed an extension of classical SIR models by multiple groups which can be considered as, for example, age groups or locally related groups [26]. Using fractional differential operators, Xu and co-authors analyzed the spread of COVID-19 in 2020 with respect to the United States by means of a fractional-order susceptible-exposed-infected-recovered (SEIR) model [27]. Regarding parameter identification problems in epidemiological models, Marinov and Marinova designed adaptive SIR models to solve these inverse problems [28,29]. In context of inverse problems, Comunian, Gaburro and Giudici concluded that high-quality data are needed to calibrate constant parameters of epidemiological models [30]. Other interesting lines of research concern the consideration of epidemics on networks [31,32,33,34,35] or application of deep-learning approaches to, for example, forecast time-series data of epidemics by these methods [36,37,38].

    One important aspect in epidemiological models is preservation of positivity. It plays a huge role in different scientific problems such as wave equations [39], simulations of chemical reactions [7], population dynamics [12,13,14] or other biological systems [3]. However, many classical time discretization schemes suffer from conserving non-negativity for arbitraty time step sizes [40]. Hence, designing non-negativity preserving numerical solution schemes for such problems can be regarded as an art as stated by Mickens [41]. For these reasons, Wacker and Schlüter examined a numerical solution scheme

    {Sh,j+1Sh,jhj+1=αj+1Sh,j+1Ih,j+1N,Ih,j+1Ih,jhj+1=αj+1Sh,j+1Ih,j+1Nβj+1Ih,j+1,Rh,j+1Rh,jhj+1=βj+1Ih,j+1,Sh,1=S0,Ih,1=I0,Rh,1=R0 (1.2)

    for (1.1) based on implicit Eulerian time discretization in [15] whose algorithm is presented in Algorithm 1.

    Algorithm 1 Algorithmic summary for implicit Eulerian finite-difference-method (1.2) for (1.1)
    1: Inputs
    2: Time vector (t1,,tM)TRM
    3: Time-varying transmission rates (α1,,αM)TRM
    4: Time-varying recovery rates (β1,,βM)TRM
    5: Initialize S:=0,I:=0,R:=0RM
    6: Initial conditions S1:=S1, I1:=I1 and R1:=R1
    7: Total population size N:=S1+I1+R1
    8: Implicit Eulerian Finite-Difference-Method
    9: for j{1,,M1} do
    10:  Define hj+1:=tj+1tj as current time step size
    11:  Define Aj+1:=(1+βj+1hj+1)(αj+1hj+1)
    12:  Define Bj+1:=(1+βj+1hj+1)Nαj+1hj+1(Sj+Ij)2
    13:  Compute Ij+1:=Bj+1Aj+1+B2j+1A2j+1+NIjAj+1
    14:  Compute Sj+1:=Sj1+αj+1hj+1Ij+1N
    15:  Compute Rj+1:=Rj+βj+1hj+1Ij+1
    16: end for
    17: Outputs
    18: Calculated vectors S,I,RRM

    Such non-standard finite-difference-methods for time discretization are also important in other application areas such as magnetohydrodynamics [42]. Here, we use f(tj):=fj as an abbreviation for time-continuous functions at time points tj and fh(tj):=fh,j as an abbreviation for time-discrete functions at time time points tj on possibly non-equidistant meshes t1<t2<<tM1<tM. Although Algorithm 1 preserves all desired properties of the time-continuous model (1.1) as shown in [15], there are still some disadvantages:

    1) From its formulation (1.1), there is to solve a quadratic equation

    Aj+1I2j+1+Bj+1Ij+1NIj=0

    where the a-priori knowledge of non-negative solutions from the time-continuous model is used to rule out one of both possible solutions for Algorithm 1 to obtain unique solvability;

    2) In each time step, we must recalculate the auxiliary quantities Aj+1 and Bj+1;

    3) By both aforementioned arguments, we conclude that Algorithm 1 does not intrinsically calculate biologically correct solutions and, from an algorithm point of view, recalculation of these auxiliary quantities is undesirable.

    We want to propose a different discretization by non-standard finite-difference-methods based on non-local approximations. To explain the idea of non-standard finite-difference-methods based on non-local approximations, we consider a time-continuous dynamical system

    y(t)=f(t,y(t)).

    Standard time-discretizations normally approximate the right-hand-side function by function values of y(t) at one previous or the current time point. Non-standard finite-difference-methods based on non-local approximations, on the contrary, approximate f(t,y(t)) by function values from more then solely one previous or the current time point. For further details, we refer to the book [41] by Mickens. For the aforementioned three reasons, we suggest a non-standard finite-difference-method (NSFDM) given by

    {Sh,j+1Sh,jhj+1=αj+1Sh,j+1Ih,jN,Ih,j+1Ih,jhj+1=αj+1Sh,j+1Ih,jNβj+1Ih,j+1,Rh,j+1Rh,jhj+1=βj+1Ih,j+1,Sh,1=S0,Ih,1=I0,Rh,1=R0 (1.3)

    in Section 3 as our first main contribution, after summarizing analytical properties of the time-continuous problem formulation (1.1) in Section 2. In Section 3, we additionally prove unconditional preservation of non-negativity and linear convergence of (1.3) towards the time-continuous solution of (1.1). Additionally, (1.3) transfers to a uniquely solvable algorithm which preserves non-negativity intrinsically. Based on (1.3), we design a numerical algorithm to solve the inverse problem of finding the time-varying parameter functions in Section 4 as our next main contribution. Finally, we strengthen our theoretical findings in Section 5 by providing some numerical examples, especially one numerical example where linear convergence is stressed, in contrast to [15], where linear convergence was not shown numerically.

    Following [15], we take the following assumptions into consideration with regard to our time-continuous model (1.1):

    (1). The total population size N is fixed for all time t0, i.e., it holds

    N(t)=N=S0+I0+R0 (2.1)

    for all t0 and we assume I0>0 to really get an evolution in time of the infected subgroup of the population;

    (2). We divide the total population into three homogeneous subgroups, namely susceptible people (S), infected people (I) and recovered people (R). The equation

    N(t)=S(t)+I(t)+R(t) (2.2)

    is valid for all t0;

    (3). The time-varying transmission rate α:[0,)[0,) is at least continuously differentiable once and there exist positive constants αmin>0 and αmax>0 such that

    αminα(t)αmax (2.3)

    holds for all t0;

    (4). The time-varying recovery rate β:[0,)[0,) is at least continuously differentiable once and there exist positive constants βmin>0 and βmax>0 such that

    βminβ(t)βmax (2.4)

    holds for all t0.

    We summarize the following analytical properties of the time-continuous problem formulation (1.1) from article [15]:

    Theorem 1. Let all assumptions from (2.1)(2.4) for our time-continuous model (1.1) be fulfilled. The following statements hold true:

    (1). Possible solutions of (1.1) remain non-negative and bounded above, i.e.,

    {0S(t)N;0I(t)N;0R(t)N (2.5)

    hold for all t0;

    (2). The time-continuous problem formulation (1.1) possesses exactly one globally unique solution for all t0;

    (3). First, S is monotonically decreasing and there exists S>0 such that limtS(t)=S. Secondly, R is monotonically increasing and there exists R>0 such that limtR(t)=R. Finally, it holds limtI(t)=0.

    Proof. (1). This statement's proof can be found in [15, Theorem 4].

    (2). Globally unique existence in time is proven in [15, Theorem 6].

    (3). Proof of the solution components' monotonicity and its long-time behavior is given in [15, Theorem 8].

    We want to note that S and R depend on the initial conditions.

    Let 0=t1<t2<<tM=T be an arbitrary and possibly non-equidistant partition of the simulation interval [0,T] with final simulation time T. As abbreviations, we write f(tj):=fj for time-continuous functions and fh(tj):=fh,j for time-discrete functions at time points tj for all j{1,2,,M}. The time-discrete problem formulation of our time-continuous model (1.1) is given by (1.3) for all j{1,2,,M1}. Here, hj+1:=tj+1tj denote non-equidistant time step sizes for all j{1,2,,M1}. Additionally, the supremum norm on [0,T] for time-continuous functions is denoted by

    f(t):=supt[0,T]|f(t)|

    while the same supremum norm on [tp,tp+1] reads

    f(t),p+1:=supt[tp,tp+1]|f(t)|.

    As our first result, our time-discrete problem formulation (1.3) conserves total population size N for all time points tj[0,T] with j{1,2,,M}.

    Theorem 2. Possible solutions of (1.3) fulfill

    N=Sh,j+Ih,j+Rh,j (3.1)

    for all j{1,2,,M}.

    Proof. This statement can be proven by induction. For j=1, it is clear by our initial conditions that

    N=Sh,1+Ih,1+Rh,1

    holds. Let us assume that

    N=Sh,j+Ih,j+Rh,j

    is valid for an arbitrary j{1,2,,M1}. Adding all three equations of (1.3), we obtain

    (Sh,j+1Sh,j)+(Ih,j+1Ih,j)+(Rh,j+1Rh,j)hj+1=0

    and this implies

    Sh,j+1+Ih,j+1+Rh,j+1=Sh,j+Ih,j+Rh,j

    which proves our assertion (3.1).

    As our next result, we show that approximate solutions of our time-continuous model (1.1) from our discretization model (1.3) remain non-negative and bounded.

    Theorem 3. Possible solutions of (1.3) remain non-negative and bounded for all tj[0,T] with arbitrary j{1,2,,M}, i.e., these solultions fulfill

    {0Sh,jN;0Ih,jN;0Rh,jN (3.2)

    for all j{1,2,,M}.

    Proof. (1). By the first three equations of (1.3), we obtain

    Sh,j+1=Sh,j1+hj+1αj+1Ih,jN (3.3)

    for all j{1,2,,M1},

    Ih,j+1=Ih,j1+hj+1αj+1Sh,j+1Ih,jN1+hj+1βj+1 (3.4)

    for all j{1,2,,M1} and

    Rh,j+1=Rh,j+hj+1βj+1Ih,j+1 (3.5)

    for all j{1,2,,M1}.

    (2). By our assumption of non-negative initial values Sh,1,Ih,1,Rh,1 and by the three equations (3.3)–(3.5), we conclude that

    Sh,j0;Ih,j0;Rh,j0

    hold for all j{1,2,,M}.

    (3). By non-negativity and conservation of total population size (3.1) from Theorem 2, it follows that

    Sh,jN;Ih,jN;Rh,jN

    hold for all j{1,2,,M}.

    (4). Hence, all possible solutions of (1.3) remain non-negative and bounded.

    It directly follows that our numerical solution scheme (1.3) is uniquely solvable for all j{1,2,,M}.

    Theorem 4. The discretization scheme (1.3), based on the explicit solutions (3.3)(3.5), is well-defined and uniquely solvable for all j{1,2,,M}.

    Proof. (3.3)–(3.5) prove that our numerical solution scheme (1.3) is well-defined. Unique solvability is a direct consequence of these equations as well. Hence, our assertion is proven.

    Remark 1. We briefly want to note why we call solutions (3.3)–(3.5) explicit. It obviously holds

    Sh,j+1=Sh,j1+hj+1αj+1Ih,jN=NSh,jN+hj+1αj+1Ih,j (3.6)

    for all j{1,2,,M} explicitly. Plugging (3.6) into (3.4) yields

    Ih,j+1=Ih,j(1+hj+1αj+1Sh,j+1Ih,jN)1+hj+1βj+1=Ih,j(1+hj+1αj+1Sh,jIh,jN+hj+1αj+1Ih,j)1+hj+1βj+1 (3.7)

    for all j{1,2,,M} as an explicit formula. Finally, by using (3.7), we get

    Rh,j+1=Rh,j+hj+1βj+1Ih,j+1=Rh,j+hj+1βj+1Ih,j(1+hj+1αj+1Sh,jIh,jN+hj+1αj+1Ih,j)1+hj+1βj+1 (3.8)

    for all j{1,2,,M}. For these reasons, we talk about an explicit numerical solution scheme.

    We show that monotonicity properties and long-time behavior of the time-continuous problem formulation (1.1) translates to our time discretization (1.3).

    Theorem 5. 1). The sequence {Sh,j}Mj=1 is monotonically decreasing and there exists a non-negative constant Sh such that limjSh,j=Sh holds.

    2). The sequence {Rh,j}Mj=1 is monotonically increasing and there exists a non-negative constant Rh such that limjRh,j=Rh holds.

    3). It holds limjIh,j=0 if also T and hj+10 are assumed.

    Proof. (1). Since {Sh,j}Mj=1 is non-negative and bounded above by the total population size N, the inequality

    Sh,j+1=Sh,j1+hj+1αj+1Ih,jNSh,j

    from (3.6) implies that this sequence is also monotonically decreasing which proves our first claim.

    (2). Since {Rh,j}Mj=1 is non-negative and bounded above by the total population size N, the inequality

    Rh,j+1=Rh,j+hj+1βj+1Ij+1Rh,j

    from (3.5) yields that this sequence is monotonically increasing which shows our second assertion.

    (3). We conclude

    0Ij+1=Rh,j+1Rh,jhj+1βj+1Rh,j+1Rh,jhj+1βmin

    from (3.5) and this shows that our third claim is also true.

    Remark 2. Both Theorems 1 and 5 imply that our time-continuous problem formulation (1.1) and our time-discrete problem formulation (1.3) converge towards the disease-free equilibrium state in the long run.

    We start this subsection by listing all our assumptions for our main result regarding linear convergence of the time-discrete solution towards the time-continuous one:

    (A11) We consider the time interval [0,T] where

    t1=0<t2<<tM1<tM:=T

    holds;

    (A12) The initial conditions of the time-continuous and of the time-discrete problems coincide;

    (A13) The time-continuous solution functions S,I,R:[0,T]R should be twice continuously differentiable;

    (A14) The time-varying transmission rate α:[0,T][0,) and the time-varying recovery rate β:[0,T][0,) should be once continuously differentiable;

    (A15) The time-varying transmission rate and the time-varying recovery rate should be bounded, i.e., there are non-negative constants αmin,αmax,βmin,βmax such that

    0αminα(t)αmax

    and

    0βminβ(t)βmax

    hold for all t[0,T];

    (A16) Set h:=maxpNhp.

    Theorem 6. Let all assumptions (A11)–(A16) be fulfilled. Then the time-discrete solution convergences linearly towards the time-continuous solution if h0.

    Proof. We shortly explain our proof's strategy because it is relatively technical. If we first assume that our time-discrete solution coincides with the time-continuous solution at a certain time point tp[0,T] for an arbitrary p{1,2,,M1}, then we investigate the local error propagation to the next time point tp+1. Secondly, we consider error propagation in time and finally, we examine accumulation of these errors. We denote time-discrete solutions, for example, by Sh,p and time-continuous solutions by S(tp) at the same time point tp.

    1) For investigation of local errors, we assume that

    (tp,Sh,p)=(tp,S(tp));(tp,Ih,p)=(tp,I(tp))and(tp,Rh,p)=(tp,R(tp))

    hold for an arbitrary p{1,2,,M1} on the time-interval [tp,tp+1]. Since we only take one time step into account, we denote corresponding time-discrete solutions by ~Sh,p+1, ~Ih,p+1 and ~Rh,p+1.

    1.1) We have by (3.6) from Remark 1 that

    ~Sh,p+1=S(tp)(1+αp+1hp+1I(tp)N)=S(tp)S(tp)αp+1hp+1I(tp)N(1+αp+1hp+1I(tp)N) (3.9)

    holds. This implies

    |S(tp+1)~Sh,p+1|(3.9)=|S(tp+1)S(tp)+S(tp)αp+1hp+1I(tp)N(1+αp+1hp+1I(tp)N)||tp+1tpS(τ)dτhp+1S(tp)|=:IS,1+|hp+1S(tp)+S(tp)αp+1hp+1I(tp)N(1+αp+1hp+1I(tp)N)|=:IIS,1. (3.10)

    By the mean value Theorem, there exists ξS,1(tp,tp+1) such that we obtain

    |S(ξS,1)|=|S(τ)S(tp)τtp|S(t). (3.11)

    This yields

    IS,1=|tp+1tp{S(τ)S(tp)}dτ|=|tp+1tp(S(τ)S(tp))(τtp)(τtp)dτ|(3.11)12h2p+1S(t). (3.12)

    For IIS,1, we notice that

    IIS,1=|hp+1S(tp)+S(tp)αp+1hp+1I(tp)N(1+αp+1hp+1I(tp)N)|(1.1)=|αphp+1S(tp)I(tp)N+S(tp)αp+1hp+1I(tp)N(1+αp+1hp+1I(tp)N)|=|hp+1S(tp)N||αpI(tp)+αp+1I(tp)(1+αp+1hp+1I(tp)N)|hp+1|αpI(tp)(1+αp+1hp+1I(tp)N)+αp+1I(tp)(1+αp+1hp+1I(tp)N)|hp+1|(αp+1αp)I(tp)(1+αp+1hp+1I(tp)N)|+hp+1|αpαp+1hp+1I(tp)I(tp)N(1+αp+1hp+1I(tp)N)|hp+1N|αp+1αp|=:IIIS,1+h2p+1α2maxN

    and hence,

    IIS,Ihp+1N|αp+1αp|=:IIIS,1+h2p+1α2maxN (3.13)

    holds due to boundedness of time-continuous solutions. Using again the mean value theorem for IIIS,1, we see that there is ξα,1(tp,tp+1) such that we obtain

    |α(ξα,1)|=|αp+1αptp+1tp|hp+1hp+1α(t). (3.14)

    Hence, we conclude

    IIIS,1=|(αp+1αp)|(3.14)hp+1α(t) (3.15)

    for IIIS,1. Plugging (3.15) into (3.13) yields

    IIS,1hp+1NIIIS,1+h2p+1α2maxN(3.15)h2p+1Nα(t)+h2p+1α2maxN=h2p+1(α(t)N+α2maxN). (3.16)

    Thus, we finally obtain

    |S(tp+1)~Sh,p+1|(3.10)=IS,1+IIS,112h2p+1S(t)+h2p+1(α(t)N+α2maxN)=(12S(t)+α(t)N+α2maxN)=:Cloc,Sh2p+1. (3.17)

    1.2) By (3.7) from Remark 1, we get

    ~Ih,p+1=I(tp)(1+αp+1hp+1~Sh,p+1N)(1+βp+1hp+1). (3.18)

    Hence, it follows

    |I(tp+1)~Ih,p+1|(3.18)=|I(tp+1)I(tp)(1+αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)|=|{I(tp+1)I(tp)}+{I(tp)I(tp)(1+αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)}|=|tp+1tpI(τ)dτ+I(tp)(βp+1hp+1αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)||tp+1tpI(τ)dτhp+1I(tp+1)|=:II,1+|hp+1I(tp+1)+I(tp)(βp+1hp+1αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)|=:III,1. (3.19)

    By the mean value theorem, there exists ξI,1(tp,tp+1) such that

    I(ξI,1)=I(τ)I(tp+1)τtp+1 (3.20)

    is valid. This implies

    II,1=|tp+1tp(I(τ)I(tp+1))(τtp+1)(τtp+1)dτ|(3.20)=|tp+1tpI(ξI,1)(τtp+1)dτ|12I(t)h2p+1. (3.21)

    For III,1, we observe

    III,1=|hp+1I(tp+1)+I(tp)(βp+1hp+1αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)|=hp+1|αp+1I(tp+1)S(tp+1)Nβp+1I(tp+1)+I(tp)(βp+1hp+1αp+1hp+1~Sh,p+1N)(1+βp+1hp+1)|=hp+11+βp+1hp+1|αp+1I(tp+1)S(tp+1)N(1+βp+1hp+1)βp+1I(tp+1)(1+βp+1hp+1)+βp+1I(tp)αp+1I(tp)~Sh,p+1N| (3.22)

    and can conclude

    III,1(3.22)hp+1|αp+1N(I(tp+1)S(tp+1)I(tp)~Sh,p+1)|=:IIII,1+hp+1|αp+1βp+1hp+1I(tp+1)S(tp+1)N|=:IVI,1+hp+1|βp+1(I(tp)I(tp+1))|=:VI,1+hp+1|β2p+1I(tp+1)hp+1|=:VII,1. (3.23)

    By boundedness and the mean value theorem, we receive the following estimates

    VII,1hp+1Nβ2max,VI,1hp+1βmaxI(t),IVI,1hp+1Nαmaxβmax (3.24)

    for VII,1, VI,1 and IVI,1. By boundedness, the triangle inequality and the mean value theorem, we can deduce

    IIII,1=|αp+1N||{I(tp+1)S(tp+1)I(tp)S(tp+1)}+{I(tp)S(tp+1)I(tp)~Sh,p+1}|αmaxN|I(tp+1)I(tp)||S(tp+1)|+αmaxN|S(tp+1)~Sh,p+1||I(tp)|(3.17)αmaxhp+1I(t)+αmaxh2p+1Cloc,S (3.25)

    and consequently, this implies

    III,1hp+1{IIII,1+IVI,1+VI,1+VII,1}hp+1{αmaxhp+1I(t)+αmaxh2p+1Cloc,S+αmaxβmaxhp+1N+βmaxhp+1I(t)+β2maxhp+1N}. (3.26)

    Hence, we conclude that

    |I(tp+1)~Ih,p+1|(3.19)II,1+III,1(3.26)12h2p+1I(t)+h2p+1{αmaxI(t)+αmaxhp+1Cloc,S+αmaxβmaxN+βmaxI(t)+β2maxN} (3.27)

    holds. By defining

    Cloc,I:={12I(t)+αmaxI(t)+αmaxhp+1Cloc,S+αmaxβmaxN+βmaxI(t)+β2maxN}, (3.28)

    we finally deduce

    |I(tp+1)~Ih,p+1|(3.28)h2p+1Cloc,I (3.29)

    from (3.27).

    1.3) By (3.8) from Remark 1, we get

    ~Rh,p+1=R(tp)+hp+1βp+1~Ih,p+1. (3.30)

    Hence, it follows

    |R(tp+1)~Rh,p+1|(3.30)=|R(tp+1)R(tp)hp+1βp+1~Ih,p+1||tp+1tpR(τ)dτhp+1βp+1I(tp+1)|+hp+1βmax|I(tp+1)~Ih,p+1|. (3.31)

    By using similar argument as in previous steps with the help of the mean value theorem and (3.29), we can deduce

    |R(tp+1)~Rh,p+1|12h2p+1R(t)+h3p+1βmaxCloc,I=h2p+1{12R(t)+βmaxCloc,Ihp+1}=:Cloc,R. (3.32)

    1.4) By setting

    Cloc:=max{Cloc,S,Cloc,I,Cloc,R}, (3.33)

    we conclude

    Ap+1:=max{|S(tp+1)~Sh,p+1|,|I(tp+1)~Ih,p+1|,|R(tp+1)~Rh,p+1|}Cloch2p+1. (3.34)

    2) Normally, the points (tp,Sp), (tp,Ip) and (tp,Rp) do not exactly lie on the graph of the time-continuous solution. We then must investigate how procedural errors such as |Sh,pS(tp)|, |Ih,pI(tp)| or |Rh,pR(tp)| propagate to the (p+1)-th time step.

    2.1) We observe that

    |Sh,p+1~Sh,p+1|=|(Sh,pSh,pαp+1hp+1Ih,pN1+αp+1hp+1Ih,pN)(S(tp)S(tp)αp+1hp+1I(tp)N1+αp+1hp+1I(tp)N)||Sh,pS(tp)|+αmaxhp+1NIS,2 (3.35)

    holds where IS,2 is given and estimated by

    IS,2=|Sh,pIh,p(1+αp+1hp+1I(tp)N)S(tp)I(tp)(1+αp+1hp+1Ih,pN)(1+αp+1hp+1Ih,pN)(1+αp+1hp+1I(tp)N)||Sh,pIh,pS(tp)I(tp)|=:IIS,2+αmaxhp+1N|Sh,pIh,pI(tp)S(tp)I(tp)Ih,p|=:IIIS,2. (3.36)

    We have

    IIS,2=|Sh,pIh,pS(tp)I(tp)||Sh,p(Ih,pI(tp))|+|I(tp)(Sh,pS(tp))|N|Ih,pI(tp)|+N|Sh,pS(tp)| (3.37)

    and

    IIIS,2=|Sh,pIh,pI(tp)S(tp)I(tp)Ih,p|=|I(tp)(Sh,pIh,pS(tp)Ih,p)|N|Ih,p(Sh,pS(tp))|N2|Sh,pS(tp)|. (3.38)

    Plugging (3.37) and (3.38) into (3.36) yields

    IS,2IIS,2+αmaxhp+1NIIIS,2N|Ih,pI(tp)|+N|Sh,pS(tp)|+αmaxhp+1N|Sh,pS(tp)|=N|Ih,pI(tp)|+N(1+αmaxhp+1)|Sh,pS(tp)|. (3.39)

    Using (3.35), we obtain

    |Sh,p+1~Sh,p+1||Sh,pS(tp)|+αmaxhp+1NIS,2(1+αmaxhp+1+(αmaxhp+1)2)|Sh,pS(tp)|+αmaxhp+1|Ih,pI(tp)|. (3.40)

    2.2) We see that

    |Ih,p+1~Ih,p+1|=|(Ih,pIh,p(βp+1hp+1αp+1hp+1Sh,p+1N)1+βp+1hp+1)(I(tp)I(tp)(βp+1hp+1αp+1hp+1~Sh,p+1N)1+βp+1hp+1)| (3.41)

    holds and get

    |Ih,p+1~Ih,p+1||Ih,pI(tp)|+βmaxhp+1|Ih,pI(tp)|+αmaxhp+1N|Ih,pSh,p+1I(tp)~Sh,p+1||Ih,pI(tp)|+βmaxhp+1|Ih,pI(tp)|+αmaxhp+1N|Ih,pSh,p+1I(tp)Sh,p+1|+αmaxhp+1N|I(tp)Sh,p+1I(tp)~Sh,p+1|(1+hp+1(αmax+βmax))|Ih,pI(tp)|+αmaxhp+1|Sh,p+1~Sh,p+1|. (3.42)

    Plugging (3.40) into (3.42) yields

    |Ih,p+1~Ih,p+1|(1+hp+1(αmax+βmax))|Ih,pI(tp)|+αmaxhp+1{(1+αmaxhp+1+(αmaxhp+1)2)|Sh,pS(tp)|+αmaxhp+1|Ih,pI(tp)|}=(1+hp+1(αmax+βmax)+α2maxh2p+1)|Ih,pI(tp)|+(αmaxhp+1+(αmaxhp+1)2+(αmaxhp+1)3)|Sh,pS(tp)|. (3.43)

    2.3) We obtain

    |Rh,p+1~Rh,p+1||Rh,pR(tp)|+βmaxhp+1|Ih,p+1~Ih,p+1|(3.43)|Rh,pR(tp)|+(βmaxhp+1+βmaxh2p+1(αmax+βmax)+βmaxα2maxh3p+1)|Ih,pI(tp)|+(βmaxαmaxh2p+1+βmaxα2maxh3p+1+βmaxα3maxh4p+1)|Sh,pS(tp)| (3.44)

    2.4) For our summary, we define

    Bp+1:=max{|Sh,p+1~Sh,p+1|,|Ih,p+1~Ih,p+1|,|Rh,p+1~Rh,p+1|} (3.45)

    for all p{0,1,,M1} and

    Dp:=max{|Sh,pS(tp)|,|Ih,pI(tp)|,|Rh,pR(tp)|} (3.46)

    for all p{1,,M}. By (3.40), (3.43) and (3.44), we define the constants

    CS,prop:=1+hp+12αmax+h2p+1α2max=1+hp+1(2αmax+hp+1α2max)=:~CS,prop;CI,prop:=1+hp+1(2(αmax+βmax)+2α2maxhp+1+α3maxh2p+1)=:~CI,prop;CR,prop:=1+hp+1(βmax+2βmax(αmax+βmax)hp+1+2βmaxα2maxh2p+1+βmaxα3maxh3p+1)=:1+hp+1~CR,prop

    and

    Cprop:=max{~CS,prop,~CI,prop,~CR,prop}. (3.47)

    Hence, it holds

    Bp+1(1+hp+1Cprop)Dp. (3.48)

    3) We obtain

    Dp+1Bp+1+Ap+1(1+hp+1Cprop)Dp+Cloch2p+1(1+hp+1Cprop)((1+hpCprop)Dp1+Cloch2p)+Cloch2p+1 (3.49)

    and inductively

    Dp+1exp(CpropT)D1+exp(CpropT)ClochT (3.50)

    which proves linear convergence of the time-discrete solution towards the time-continuous solution.

    Our algorithm for our proposed non-standard finite-difference-method for (1.1) is portrayed in Algorithm 2 below.

    Algorithm 2 Algorithmic summary for our proposed non-standard finite-difference-method (3.2) for (1.1)
    1: Inputs
    2: Time vector (t1,,tM)TRM
    3: Time-varying transmission rates (α1,,αM)TRM
    4: Time-varying recovery rates (β1,,βM)TRM
    5: Initialize S:=0,I:=0,R:=0RM
    6: Initial conditions S1:=S1, I1:=I1 and R1:=R1
    7: Total population size N:=S1+I1+R1
    8: Non-Standard Finite-Difference-Method
    9: for j{1,,M1} do
    10:  hj+1:=tj+1tj
    11:  Sj+1:=Sj1+hj+1αj+1IjN from (3.6)
    12:  Ij+1:=Ij+hj+1αj+1Sj+1IjN1+hj+1βj+1 from (3.7)
    13:  Rj+1:=Rj+hj+1βj+1Ij+1 from (3.8)
    14: end for
    15: Outputs
    16: Calculated vectors S,I,RRM

    We consider the parameter identification problem (1.3) for all j{1,2,,M1} where we take the following assumptions into account:

    (A21) The sequences {Sh,p}Mp=1, {Ih,p}Mp=1 and {Rh,p}Mp=1 are given;

    (A22) It holds 0Sh,pN for all p{1,,M} and the sequence {Sh,p}Mp=1 is monotonically decreasing;

    (A23) It holds 0Ih,pN for all p{1,,M};

    (A24) It holds 0Rh,pN for all p{1,,M} and the sequence {Rh,p}Mp=1 is monotonically increasing;

    (A25) We assume Sh,p0, Ih,p0 and Rh,p0 for all p{1,,M}.

    Our idea now is to reduce (1.3) to

    {Sh,p+1Sh,php+1=αp+1Sh,p+1Ih,pN;Rh,p+1Rh,php+1=βp+1Ih,p+1 (4.1)

    for all p{1,,M1}. Hence, we obtain the sought time-varying transmission rate and the sought time-varying recovery rate by

    {αp+1=NSh,p+1Ih,p(Sh,pSh,p+1)hp+1;βp+1=1Ih,p+1(Rh,p+1Rh,p)hp+1 (4.2)

    for all p{1,,M1}. Finally, we have explicit formulas for the time-varying transmission and recovery rates at every time point which we can evaluate by the known data from the numbers of susceptible, infected and recovered people. We have the following theorem.

    Theorem 7. Let all assumptions (A21)–(A25) be fulfilled. (4.1) for parameter identification is uniquely solvable for all p{1,,M1} and it holds αp+10 and βp+10 for all p{1,,M1}.

    Proof. 1) Unique solvability is a direct consequence of (4.2).

    2) {Sh,p}Mp=1 is monotonically decreasing. Hence, Sh,pSh,p+10 for all p{1,,M1} and we have

    αp+1=NSh,p+1Ih,p(Sh,pSh,p+1)hp+10.

    3) {Rh,p}Mp=1 is monotonically increasing. Hence, Rh,p+1Rh,p0 for all p{1,,M1} and we have

    βp+1=1Ih,p+1(Rh,p+1Rh,p)hp+10.

    This finishes our claim's proof.

    Our algorithmic summary for our proposed parameter identification problem (4.2) reads:

    Algorithm 3 Algorithmic summary for our proposed parameter identification algorithm for (4.2)
    1: Inputs
    2: Time vector (t1,,tM)TRM
    3: Sequence of susceptible population {Sh,p}Mp=1 saved in one vector SRM
    4: Sequence of infected population {Ih,p}Mp=1 saved in one vector IRM
    5: Sequence of recovered population {Rh,p}Mp=1 saved in one vector RRM
    6: Constant total population size N:=S1+I1+R1
    7: Initialize vectors α:=0RM and β:=0RM
    8: Parameter Identification Algorithm
    9: for j{1,,M1} do
    10:  hj+1:=tj+1tj
    11:  αj+1:=NSh,j+1Ih,j(Sh,jSh,j+1)hj+1
    12:  βj+1=1Ih,j+1(Rh,j+1Rh,j)hj+1
    13: end for
    14: Outputs
    15: Calculated vectors α,βRM

    In this section, we want to strengthen our theoretical findings by two numerical examples. We apply GNU OCTAVE for our implementation [43].

    The initial conditions for our first example read S(0)=5000, I(0)=5000, R(0)=0, N=10,000, α=0.5, β=0.1 and our simulation interval is given by [0,T] with T=70. We compare three numerical algorithms, namely our proposed non-standard finite-difference-method (NSFDM), the explicit Eulerian scheme (EE) and an explicit Runge-Kutta scheme with two stages (RK2) and use equidistant time step sizes h for our computations.

    As it can be clearly seen in Figures 1 and 2, only our novel non-standard finite-difference-method is unconditionally non-negativity-preserving and stable. Both explicit standard time-discretizations suffer from time-step restrictions to obtain non-negativity preservation. In Figure 3, we observe that all three numerical algorithms possess same properties for smaller time step sizes h. On the positive side for all algorithms, they conserve total population size N as depicted in Figure 4.

    Figure 1.  Example 1: Instabilities for time step size h=7.5 for (EE, not shown) and (RK2, shown).
    Figure 2.  Example 1: Instabilities and negativity for time step size h=5 for (EE) and (RK2).
    Figure 3.  Example 1: Similar behavior of all three algorithms for time step size h=0.1.
    Figure 4.  Example 1: Total population size conservation of all three algorithms for time step size h=0.1.

    Finally, underlining our convergence result from Theorem 6, we compare results of our non-standard finite-difference-method (NSFDM) for different time step sizes h with a fine scale Runge-Kutta scheme of order 4 (RK4) at T=70 where a fine time step size of 0.0001 is applied for (RK4). The errors

    ● Error for S(t): |SNSFDM,MSRK4,M|;

    ● Error for I(t): |INSFDM,MIRK4,M|;

    ● Error for R(t): |RNSFDM,MRRK4,M|

    are used for this purpose. It can be clearly seen from Table 1 that the theoretical convergence order is achieved by our non-standard finite-difference-method.

    Table 1.  Errors for example 1 with (NSFDM).
    h 0.03125 0.0625 0.125 0.25 0.5 1.0
    Error for S(t) 0.27673 0.55049 1.0889 2.1307 4.0817 7.5129
    Error for I(t) 0.14805 0.2971 0.59806 1.2115 2.4843 5.2145
    Error for R(t) 0.41436 0.83717 1.6766 3.3317 6.5556 12.717

     | Show Table
    DownLoad: CSV

    We consider real-world data from Spain [44]. N=47,370,000 is the total population size of Spain. The cumulative cases of infected people are modified such

    S(t)=NI(t)R(t);I(t)=Nconfirmed(t)Ndead(t)Nrecovered(t);R(t)=Ndead(t)+Nrecovered(t)

    hold from the given data. We take α(t)=0.52e0.03t and β(t)=0.045. For our simulation, we additionally assume h=0.75 as an equidistant time step size.

    Our estimated transmission rate α(t) and constant recovery rate β(t) are user-chosen and adapted to the data in Figures 6 and 7, while the modified data for infected and recovered people are depicted in Figure 5. We solely consider the beginning of the pandemic because, later, vaccines have been available and reinfections have occurred after virus modifications. In Figure 8, we see results of our numerical simulations with h=0.75. Results are relatively sensitive with respect to time step sizes and estimates rates, e.g., time-varying transmission rates. Hence, we can only conclude that good data acquisition and different predictions in different settings are crucial for future pandemics to make predictions for courses of such future epidemics.

    Figure 5.  Example 2: Data for infected (I(t)) and recovered (R(t)) from Spain.
    Figure 6.  Example 2: Estimated time-varying transmission rate (α(t)) from data.
    Figure 7.  Example 2: Estimated time-varying recovery rate (β(t)) from data.
    Figure 8.  Example 2: Numerical simulation for estimated rates.

    In this article, we first summarized some analytical properties of a time-continuous epidemiological model (1.1) as given in [15]. Afterwards, we designed a new non-standard finite-difference-method (1.3) as a time-discrete version of the continuous model. In Section 3, we contributed our main results on our proposed non-standard finite-difference-method (1.3). Namely, we investigated unconditionally non-negativity preservation, conservation of total population size, convergence towards a disease-free equilibrium point and linear convergence by letting the time size h0. Conclusively for our theoretical findings, we developped a simple parameter identification algorithm in Section (4). In Section 5, we gave two numerical examples to underline our theoretical findings. Comparing Algorithms 1 and 2, we conclude that the latter one is definitely easier to implement and it can serve as a starting point for constructing higher order time discretization schemes for (1.1). Regarding practical applications, our proposed time-discretization by a non-standard finite-difference-method preserves all desired properties from the time-continuous model which are expected from our real-word intuition. Additionally, the simple parameter identification algorithm produce fast graphs from given data where trends in time-varying transmission rates such as contact restrictions might be seen from.

    There might be different directions to extend our work:

    ● It seems straightforward to integrate further compartments into our model such that we can additionally investigate influences such as, for example, vaccines or the simple extension to the SEIR model. For example, we readily can construct

    {Sh,j+1Sh,jhj+1=αj+1Sh,j+1Eh,jN,Eh,j+1Eh,jhj+1=αj+1Sh,j+1Eh,jNγj+1Eh,j+1,Ih,j+1Ih,jhj+1=γj+1Eh,j+1βj+1Ih,j+1,Rh,j+1Rh,jhj+1=βj+1Ih,j+1,Sh,1=S0,Eh,1=E0,Ih,1=I0,Rh,1=R0 (6.1)

    as one variant of a non-standard finite-difference-method for the SEIR model and it follows directly that this scheme conserves total population size N and can be written in an explicit fashion as our proposed non-standard finite-difference-method for our considered SIR model by

    {Sh,j+1=Sh,j1+hj+1αj+1Eh,jN,Eh,j+1=Eh,j+hj+1αj+1Sh,j+1Eh,jN1+hj+1γj+1,Ih,j+1=Ih,j+hj+1γj+1Eh,j+11+hj+1βj+1,Rh,j+1=Rh,j+hj+1βj+1Ih,j+1 (6.2)

    to see that it also preserves non-negativity assuming positive initial conditions. One disadvantage is that there are different possibilities to construct such non-standard finite-difference-methods by non-local approximations and a suitable choice depends on the time-continuous properties which should be transferred to the time-discrete case. However, as seen by this example, it is flexible to construct different possibilities of algorithms and they are easy to implement;

    ● It might be of interest to construct higher order non-standard finite-difference-methods from our first-order non-standard finite-difference-method in order to get higher accuracy although, especially, our second example demonstrated that predictions of such models need to be considered with care. One straightforward way to improve accuracy, and hence, the convergence order of numerical solution schemes is application of Richardson's extrapolation [45];

    ● One can use our discretization model for the discretization of optimal control problems for minimizing certain epidemic aspect such as eradication time [46].

    Our code and used data from [44] can be found under https://github.com/bewa87/2023-SIR-FirstOrder-NSFDM.

    We thank the editor and both anonymous reviewers for their valuable comments which definitely helped us to improve quality and readability of our manuscript.

    The authors declare there is no conflict of interest.

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